Idiopathic Pulmonary Fibrosis

Respiratory Disease MONDO:0800504 Pathograph 13 Show in embeddings browser Respiratory Disease Lung Disease

A chronic progressive fibrosing interstitial pneumonia of unknown cause, characterized by usual interstitial pneumonia pattern, irreversible loss of lung architecture, and worsening respiratory failure.

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10
Pathophys.
3
Phenotypes
3
Hypotheses
3
Gaps
13
Pathograph
4
Genes
3
Medical Actions
1
Deep Research
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Mechanistic Hypotheses

3
Injury-Centric Wound Healing Model
injury_centric_model CANONICAL
Repetitive alveolar epithelial injury is modeled as the primary upstream driver; AT2 cell senescence and subsequent fibroblast activation are downstream consequences of failed wound healing. Fibrosis represents an aberrant, non-resolving repair response to injury in genetically or environmentally susceptible individuals.
Retained as CANONICAL because it is consistent with clinical observations (cigarette smoke, infections, and micro-aspiration as risk factors) and the requirement for repeated injury rather than a single hit. However, this model does not fully explain why fibrosis persists and progresses after the initiating injury resolves.
Show evidence (1 reference)
PMID:35563849 SUPPORT Other
"it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response, during which fibroblasts differentiate into myofibroblasts."
Supports the injury-centric model in which repetitive microinjury is the upstream initiating event that leads to fibroblast activation.
Senescence-First (Stem-Cell Exhaustion) Model
senescence_first_model ALTERNATIVE
Age-related and genetically accelerated AT2 cell telomere attrition renders the alveolar epithelium incapable of normal repair; any injury triggers SASP rather than regeneration. In this model, IPF is fundamentally a stem-cell exhaustion disease in which senescent AT2 cells act as autonomous profibrotic drivers through autocrine TGF-beta feedback — even in the absence of ongoing immune activation.
Supported by the exponential age-dependence of IPF, by telomere gene mutations in familial IPF causing earlier onset, and by the Enomoto 2023 organoid model showing immune-independent fibrogenesis. However, this model alone does not explain why fibrosis is patchy or why some individuals with short telomeres do not develop IPF without injury.
Show evidence (2 references)
PMID:37653024 SUPPORT Model Organism
"the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis."
Demonstrates that AT2 cell senescence and autocrine TGF-beta are sufficient for fibrogenesis without immune involvement, consistent with the senescence-first model.
PMID:33808277 SUPPORT Other
"Loss of regenerative potential of alveolar type II epithelial cells (AT2) cells following injury has been postulated to underlie telomeropathy-associated lung fibrosis, with concomitant excessive proliferation of airway cells displaying abnormal phenotypes"
Review describes telomere-driven loss of AT2 regenerative capacity as a mechanistic explanation for the strong age and telomere-length associations in IPF.
Convergent Self-Sustaining Feedback Loop Model
feedback_loop_convergence_model ALTERNATIVE
The injury-centric and senescence-first models converge once AT2 senescence and matrix stiffness feedback are engaged. Neither entry point alone is sufficient; the system becomes self-sustaining through: the autocrine AT2 SASP TGF-beta loop that perpetuates senescence; matrix stiffness mechano-transduction (integrin/YAP-TAZ) that maintains fibroblast activation independently of new injury; and aberrant basaloid cell accumulation that prevents restoration of normal alveolar epithelium. Therapeutic intervention must target these feedback loops, not just the initiating injury, to halt progression.
Emerging as the dominant synthesis view as single-cell and organoid data accumulate. This model explains progressive disease despite removal of injury trigger, age-dependence without universal penetrance, and why neither anti-inflammatory nor single-pathway treatments have substantially changed long-term outcomes.
Show evidence (1 reference)
PMID:34813355 SUPPORT Other
"The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay of cell types and signaling pathways. Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic),..."
Annual Review of Pathology review frames IPF as a convergence of multiple predisposing factors and cell types, consistent with the feedback loop model in which no single upstream event fully explains the disease.
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Discussions and Knowledge Gaps

3
Is repetitive alveolar epithelial injury the primary upstream driver of IPF, or does age-related AT2 cell senescence and telomere attrition precede and predispose to fibrosis independently of ongoing injury?
KNOWLEDGE GAP OPEN disc_ipf_injury_vs_senescence_ordering
Attached to
pathophysiology#AT2 cell senescence and SASP
The causal ordering among epithelial injury, AT2 cell senescence, and fibroblast activation remains unresolved. In the injury-centric model, repetitive microinjury is the upstream event and senescence is a downstream consequence, implying that removing the injury source should be sufficient to halt progression. In the senescence-first model, age-related and genetic telomere attrition renders AT2 cells intrinsically unable to regenerate, so any injury triggers SASP rather than repair. The Enomoto 2023 organoid model (PMID:37653024) provides the strongest mechanistic evidence that AT2 senescence drives fibrogenesis non-inflammatorily, but it uses bleomycin as the initial stimulus, leaving open whether senescence can initiate fibrosis in the complete absence of an exogenous trigger. Clinical observations that IPF can progress in the absence of identified ongoing exposure support the senescence-first or feedback-loop models over a purely injury-dependent explanation.
What are the critical feedback loops — autocrine AT2 SASP, matrix stiffness mechano-transduction, and aberrant basaloid cell accumulation — that make IPF fibrosis self-sustaining and progressive after the initiating injury resolves, and which of these is most therapeutically tractable?
KNOWLEDGE GAP OPEN disc_ipf_ecm_feedback_irreversibility
Attached to
pathophysiology#Excessive extracellular matrix deposition pathophysiology#Aberrant basaloid cell emergence
Multiple positive feedback loops have been proposed to explain why IPF progresses even after the putative initiating injury resolves: the autocrine AT2 SASP TGF-beta loop (PMID:37653024); matrix stiffness mechano-transduction via integrin/YAP-TAZ that maintains fibroblast activation independently of soluble TGF-beta; and aberrant basaloid cell accumulation that depletes the normal AT2 stem cell pool and prevents alveolar re-epithelialization. The relative contribution of each loop to disease progression has not been established in humans. Existing approved therapies (pirfenidone and nintedanib) slow progression but do not stop or reverse fibrosis, suggesting these feedback loops are not adequately targeted. Senolytics (dasatinib + quercetin, PMID:36857968) are being evaluated as a strategy to interrupt the AT2 SASP feedback loop, but phase III efficacy data are lacking.
Does gut dysbiosis drive IPF progression (dysbiosis → fibrosis), or is it a secondary consequence of systemic inflammation and drug effects in established IPF (fibrosis → dysbiosis)? Are microbial metabolite deficits (SCFA, secondary bile acids) individually sufficient to amplify pulmonary fibrosis, or do they require cofactors? Can fecal microbiota transplantation attenuate pulmonary inflammation in human ILD?
KNOWLEDGE GAP OPEN disc_ipf_gut_lung_axis_causality
Attached to
pathophysiology#Gut dysbiosis and microbial metabolite dysregulation
Current evidence for gut-lung axis involvement in IPF is primarily from associative cross-sectional studies and preclinical bleomycin models (PMID:42294946). The directionality of the gut-lung axis relationship has not been established: dysbiosis may be upstream (amplifying fibrosis via pro-inflammatory cytokines and reduced immune tolerance) or downstream (resulting from systemic inflammation, malnutrition, or IPF medications such as nintedanib and pirfenidone that alter gut microbiota). Metabolite sufficiency experiments (butyrate or propionate supplementation in IPF models) are limited. Interventional FMT studies in animal models suggest attenuation of pulmonary inflammation, but no human clinical evidence exists. Establishing causality and metabolite specificity is required before gut-lung axis modulation can be considered a therapeutic target in IPF.
Proposed experiments
Longitudinal microbiome profiling in IPF cohorts
exp_ipf_microbiome_temporal_cohort
Longitudinal microbiome profiling in prospective IPF cohorts with time-matched lung function decline to assess whether dysbiosis precedes or follows functional deterioration, establishing causal directionality.
Germ-free and antibiotic-depleted mouse IPF models
exp_ipf_germ_free_bleomycin
Germ-free or antibiotic-depleted mouse bleomycin models to test whether microbiota depletion attenuates pulmonary fibrosis, establishing a causal contribution of gut microbiota to lung fibrotic pathways.
SCFA supplementation in IPF mouse models
exp_ipf_scfa_supplementation
SCFA (butyrate and propionate) supplementation in bleomycin-induced pulmonary fibrosis mouse models to determine whether restoring microbial metabolite levels reduces fibrotic burden and pro-inflammatory cytokines.
⚙

Pathophysiology

10
Repetitive alveolar epithelial injury and aberrant repair
Recurrent injury to alveolar epithelial cells, particularly type II pneumocytes, initiates a dysregulated wound-healing response that fails to restore normal alveolar architecture and instead drives fibrotic remodeling.
type II pneumocyte CL:0002063
wound healing GO:0042060 ↕ DYSREGULATED apoptotic process GO:0006915 ↑ INCREASED
lung UBERON:0002048
Downstream
AT2 cell senescence and SASP
Show evidence (2 references)
PMID:35563849 SUPPORT Other
"it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response, during which fibroblasts differentiate into myofibroblasts."
This review directly supports repetitive epithelial injury as the initiating trigger for maladaptive wound healing in IPF.
PMID:33201251 SUPPORT Other
"Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling."
This review links epithelial apoptosis and senescence to the abnormal remodeling response after lung injury in IPF.
AT2 cell senescence and SASP
Recurrent DNA damage and telomere attrition drive alveolar type II pneumocytes into a senescent state characterized by a senescence-associated secretory phenotype (SASP). An autocrine TGF-beta loop sustains AT2 cell senescence while paracrine SASP signals activate lung fibroblasts and recruit profibrotic macrophages, converting a transient injury response into a self-reinforcing fibrotic program.
type II pneumocyte CL:0002063
cellular senescence GO:0090398 ↑ INCREASED TGF-beta receptor signaling pathway GO:0007179 ↑ INCREASED
lung UBERON:0002048
Downstream
Profibrotic macrophage recruitment and amplification
Fibroblast activation and myofibroblast differentiation
Aberrant basaloid cell emergence
Show evidence (2 references)
PMID:37653024 SUPPORT Model Organism
"bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast..."
Demonstrates that AT2 cell senescence and autocrine TGF-beta feedback are mechanistically sufficient to drive fibroblast-to-myofibroblast differentiation without immune-cell involvement, establishing AT2 senescence as a key intermediate between injury and fibrosis.
PMID:34813355 SUPPORT Other
"Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic), leading to metabolic dysfunction, senescence, aberrant epithelial cell activation, and dysregulated epithelial repair."
Annual Review of Pathology 2022 review places AT2 senescence as a consequence of recurrent injury that bridges injury to downstream fibrotic mechanisms.
Alveolar epithelial telomere attrition
In familial and a subset of sporadic IPF, germline mutations in the telomerase components TERT and TERC (hTR) and related telomere-maintenance genes cause accelerated telomere shortening in alveolar epithelial cells. Critically short telomeres in type II pneumocytes provoke a persistent DNA-damage response and replicative senescence, linking IPF to the telomere biology of the short-telomere syndromes (including dyskeratosis congenita).
type II pneumocyte CL:0002063
telomere maintenance GO:0000723 ↓ DECREASED DNA damage response GO:0006974 ↑ INCREASED
lung UBERON:0002048
Downstream
AT2 cell senescence and SASP
AT2 progenitor exhaustion and impaired alveolar regeneration
Show evidence (2 references)
PMID:17392301 SUPPORT Human Clinical
"Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis."
Links telomerase (hTERT/hTR) mutations and the short-telomere syndromes to pulmonary fibrosis, supporting alveolar telomere attrition as an upstream driver in IPF. Evidence source is HUMAN_CLINICAL (familial genetic study).
PMID:17392301 SUPPORT Human Clinical
"To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR."
Tests short telomeres as a cause of familial IPF via telomerase-gene screening, supporting the telomere-attrition node. Evidence source is HUMAN_CLINICAL (familial genetic study).
AT2 progenitor exhaustion and impaired alveolar regeneration
Alveolar type II pneumocytes are the facultative progenitors that renew the alveolar epithelium. Telomere attrition and senescence deplete this progenitor pool and limit its self-renewal and regenerative capacity, so injured alveoli cannot be properly re-epithelialized; repair is instead diverted toward aberrant, profibrotic epithelial states.
type II pneumocyte CL:0002063
stem cell population maintenance GO:0019827 ↓ DECREASED tissue regeneration GO:0042246 ↓ DECREASED
lung UBERON:0002048
Downstream
Aberrant basaloid cell emergence
Show evidence (1 reference)
PMID:18753630 SUPPORT Human Clinical
"Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF."
Establishes that short telomeres limit lung tissue-renewal capacity, supporting exhaustion of the alveolar type II progenitor pool. Evidence source is HUMAN_CLINICAL (patient telomere-length study).
Aberrant basaloid cell emergence
A subset of AT2 cells under senescent stress fails to differentiate normally and instead adopts an aberrant basaloid state marked by KRT17 expression, epithelial-to-mesenchymal transition markers (COL1A1, FN1), senescence markers (p16, p21), and elevated integrin αVβ6 — a potent activator of latent TGF-beta. These aberrant basaloid cells are found at the epithelial-mesenchymal interface in fibrotic honeycombing and propagate a profibrotic secretome that sustains myofibroblast activation and prevents restoration of normal alveolar epithelium.
aberrant basaloid epithelial cell CL:0000646
epithelial to mesenchymal transition GO:0001837 ↑ INCREASED cellular senescence GO:0090398 ↑ INCREASED
lung UBERON:0002048
Downstream
Fibroblast activation and myofibroblast differentiation
Show evidence (2 references)
PMID:33859634 SUPPORT Human Clinical
"Within both the IPF and SSc-ILD samples we identified a small population of the recently described aberrant basaloid cells (or KRT5-/KRT17+ cells), with no cells sharing this distinct transcriptome amongst the control samples"
Single-cell RNA sequencing of explanted human IPF lungs identifies KRT5-/KRT17+ aberrant basaloid cells exclusively in fibrotic tissue, supporting their role as a disease-specific epithelial population at the interface of AT2 senescence and myofibroblast activation.
PMID:34813355 SUPPORT Other
"These studies have uncovered a novel type of AEC with characteristics of an aberrant basal cell, which may disrupt normal epithelial repair and propagate a profibrotic phenotype."
Annual Review of Pathology 2022 review identifies the aberrant basaloid cell population as mechanistically relevant to IPF pathogenesis through disruption of normal epithelial repair.
Gut dysbiosis and microbial metabolite dysregulation
Alterations in the composition and function of the gut microbiota drive dysbiosis characterized by reduced microbial diversity and decreased production of short-chain fatty acids (butyrate, propionate) and secondary bile acids. This dysbiosis impairs intestinal epithelial barrier integrity, reduces metabolites that support Foxp3+ regulatory T cells and immune tolerance, and drives a pro-inflammatory shift in the intestinal immune environment. These changes activate innate lymphoid cells and mucosal-associated invariant T cells, promoting systemic immune activation and increased circulating pro-inflammatory cytokines (TNF-α, IL-6, IL-17) that cross the gut-lung barrier to enhance lung fibrotic pathways and amplify TGF-beta-mediated fibroblast activation.
regulatory T cell CL:0000815 ↓ DECREASED enterocyte CL:0000584 innate lymphoid cell CL:0001065 ↑ INCREASED mucosal-associated invariant T cell CL:0000940 ↑ INCREASED
cell-cell adhesion GO:0098609 ⚠ ABNORMAL short-chain fatty acid metabolic process GO:0046459 ↓ DECREASED inflammatory response GO:0006954 ↑ INCREASED
large intestine UBERON:0000059 lung UBERON:0002048
Downstream
Profibrotic macrophage recruitment and amplification
Fibroblast activation and myofibroblast differentiation
Show evidence (2 references)
PMID:42294946 SUPPORT Other
"Accumulating evidence supports bidirectional gut-lung axis interactions potentially mediated by the microbiota. Alterations in the gut microbiome have been associated with the onset and severity of interstitial lung disease."
This recent review synthesizes preclinical and clinical evidence linking gut dysbiosis to IPF pathogenesis through bidirectional gut-lung axis interactions mediated by altered microbiota.
PMID:42294946 SUPPORT Other
"Preclinical studies demonstrate that gut dysbiosis is associated with altered immune responses, increased pro-inflammatory cytokines, and enhanced fibrotic pathways, with mechanistic evidence suggesting the involvement of specific microbial metabolites (short-chain fatty acids, bile acids, and..."
Preclinical and in vivo evidence demonstrates mechanistic linkages between gut dysbiosis and enhanced fibrotic pathways through dysregulated microbial metabolites and altered immune responses.
Profibrotic macrophage recruitment and amplification
Injured alveolar units recruit and activate inflammatory and monocyte-derived macrophage populations that reinforce a profibrotic repair program and help sustain fibroblast activation.
alveolar macrophage CL:0000583
inflammatory response GO:0006954 ↑ INCREASED leukocyte migration GO:0050900 ↑ INCREASED
lung UBERON:0002048
Downstream
Fibroblast activation and myofibroblast differentiation
Show evidence (2 references)
PMID:32549377 SUPPORT Other
"Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis."
This review explicitly places monocyte-derived macrophages among the major cell populations driving fibrotic progression in IPF.
PMID:38232990 SUPPORT Other
"Different cell types (epithelial cells, endothelial cells, fibroblasts and macrophages) interact dynamically through multiple signalling pathways, including biochemical/molecular and mechanical signals, such as stiffness, affecting cell function and differentiation."
This review supports dynamic macrophage cross-talk with epithelial and mesenchymal compartments in fibrotic lung disease.
Fibroblast activation and myofibroblast differentiation
Fibroblasts transition into activated myofibroblasts under the influence of TGF-beta signaling and epithelial plasticity programs, creating the central effector cell state of established IPF fibrosis.
fibroblast CL:0000057 myofibroblast CL:0000186
TGF-beta receptor signaling GO:0007179 ↑ INCREASED epithelial to mesenchymal transition GO:0001837 ↑ INCREASED
lung UBERON:0002048
Downstream
Excessive extracellular matrix deposition
Show evidence (3 references)
PMID:35563849 SUPPORT Other
"it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response, during which fibroblasts differentiate into myofibroblasts."
This review directly supports fibroblast-to-myofibroblast differentiation as a core transition downstream of epithelial injury.
PMID:32549377 SUPPORT Other
"TGF-β is a critical cytokine that drives development of fibrosis."
This review supports TGF-beta signaling as a central profibrotic pathway in IPF.
PMID:33201251 SUPPORT Other
"Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling."
This review supports epithelial-to-mesenchymal transition as part of the abnormal remodeling program in IPF.
Excessive extracellular matrix deposition
Activated myofibroblasts deposit excessive extracellular matrix proteins and collagen, producing fibroblastic foci, stiffening lung tissue, and locking the parenchyma into a self-reinforcing scar state.
myofibroblast CL:0000186
extracellular matrix organization GO:0030198 ↑ INCREASED collagen biosynthetic process GO:0032964 ↑ INCREASED
lung UBERON:0002048
Downstream
Architectural distortion and gas-exchange failure
Fibroblast activation and myofibroblast differentiation Matrix stiffness mechano-transduction (integrin/YAP-TAZ signaling) feeds back to maintain fibroblast activation independently of new injury, creating a self-sustaining fibrotic loop that persists after the initiating injury resolves.
Show evidence (2 references)
PMID:32549377 SUPPORT Other
"changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis."
This review links activated myofibroblasts directly to ECM deposition, architectural remodeling, and fibrosis in IPF.
PMID:38232990 SUPPORT Other
"Different cell types (epithelial cells, endothelial cells, fibroblasts and macrophages) interact dynamically through multiple signalling pathways, including biochemical/molecular and mechanical signals, such as stiffness, affecting cell function and differentiation."
Supports the mechano-transduction concept: matrix stiffness signals through integrin pathways to maintain fibroblast activation independently of soluble TGF-beta, providing a mechanistic basis for the feedback edge from ECM deposition back to fibroblast activation.
Architectural distortion and gas-exchange failure
Progressive scarring distorts distal lung units, reduces elastic recoil, impairs gas exchange, and culminates in respiratory failure and death.
lung UBERON:0002048
Show evidence (1 reference)
PMID:32549377 SUPPORT Other
"The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory failure and death."
This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Idiopathic Pulmonary Fibrosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Respiratory 2
Dyspnea Dyspnea HP:0002094
Sequelae: Exercise intolerance
Show evidence (1 reference)
PMID:32274173 SUPPORT Human Clinical
"Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with significant dyspnea and limited exercise capacity."
This systematic review explicitly identifies dyspnea as a major symptomatic burden in IPF.
Respiratory failure Respiratory failure HP:0002878
Show evidence (1 reference)
PMID:32549377 SUPPORT Other
"The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory failure and death."
This review directly links progressive architectural distortion in IPF to respiratory failure.
Constitutional 1
Exercise intolerance Exercise intolerance HP:0003546
Show evidence (1 reference)
PMID:32274173 SUPPORT Human Clinical
"Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with significant dyspnea and limited exercise capacity."
This systematic review explicitly identifies limited exercise capacity as a core functional limitation in IPF.
🧬

Genetic Associations

4
MUC5B (Associated)
Gene: MUC5B hgnc:7516
Show evidence (2 references)
PMID:21506741 SUPPORT Human Clinical
"A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis."
This human case-control study identifies the MUC5B promoter variant rs35705950 as a major inherited susceptibility factor for IPF.
PMID:33965873 SUPPORT Human Clinical
"Key among these were the up-regulation of TGFBI, MMP7, TNF, ADAM12, activation of immune co-stimulatory markers, toll-like receptors, and increased expression of the IPF-related gene MUC5B in both minimal and established fibrotic regions of the lungs."
This review specifically identifies increased MUC5B expression as part of the molecular program present in fibrotic IPF lung tissue.
TERT (Associated)
Gene: TERT hgnc:11730
Show evidence (2 references)
PMID:35078193 SUPPORT Human Clinical
"monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2)"
Greek national cohort identifies TERT as the most frequently mutated telomere-related gene in heritable IPF, establishing its role as a major genetic determinant of familial pulmonary fibrosis.
PMID:33808277 SUPPORT Other
"More rapidly progressive disease is observed in fibrotic ILD patients with telomere gene mutations, regardless of underlying diagnosis."
Review confirms that TERT and other telomere gene mutations confer worse prognosis in IPF, consistent with the mechanistic model of AT2 telomere dysfunction accelerating senescence.
TERC (Associated)
Gene: TERC hgnc:11727
Show evidence (2 references)
PMID:35078193 SUPPORT Human Clinical
"monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2)"
Greek national cohort identifies TERC as the second most frequently mutated telomere-related gene in heritable IPF.
PMID:33808277 SUPPORT Other
"A number of rare genetic mutations have been identified in genes encoding for components of the telomerase complex, including telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), in familial and, less frequently, in sporadic fibrotic ILDs."
Review confirms TERC mutations as a cause of familial and sporadic fibrotic ILD, consistent with the AT2 telomere shortening to senescence mechanistic model.
RTEL1 (Associated)
Gene: RTEL1 hgnc:15888
Show evidence (1 reference)
PMID:35078193 SUPPORT Human Clinical
"monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2)"
Greek national cohort identifies RTEL1 as a telomere-related gene mutated in heritable IPF, extending the genetic architecture beyond TERT/TERC to include DNA helicase function.
💊

Medical Actions

3
Pirfenidone
Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352
Agent: pirfenidone CHEBI:32016
Oral antifibrotic therapy that slows physiologic decline and improves progression-free survival in IPF.
Show evidence (1 reference)
PMID:24836312 SUPPORT Human Clinical
"Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis."
The ASCEND phase 3 trial shows pirfenidone slows clinical progression in IPF.
Nintedanib
Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352
Agent: nintedanib CHEBI:85164
Antifibrotic tyrosine kinase inhibitor that slows the rate of forced vital capacity decline in IPF.
Show evidence (1 reference)
PMID:24836310 SUPPORT Human Clinical
"In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression"
The INPULSIS phase 3 trials show nintedanib slows lung function decline in IPF.
Dasatinib and Quercetin (Senolytic Combination)
Action: Pharmacotherapy NCIT:C15986
Agent: dasatinib CHEBI:49375 quercetin CHEBI:16243
A senolytic drug combination targeting senescent cells in IPF. Dasatinib is a BCR-ABL/Src kinase inhibitor that clears senescent cells; quercetin is a flavonoid with complementary pro-apoptotic effects on senescent cells. Phase I pilot trial (NCT02874989) demonstrated feasibility and tolerability in IPF patients, supporting the rationale for larger efficacy trials.
Show evidence (1 reference)
PMID:36857968 SUPPORT Human Clinical
"IPF is associated with increased senescent cells burden, which may be alleviated with administration of senescent cell targeting drugs termed 'senolytics'"
Phase I pilot trial of the senolytic combination dasatinib + quercetin in IPF patients, establishing the rationale that reducing the senescent cell burden may slow fibrotic progression.
🔬

Biochemical Markers

1
Forced Vital Capacity (Decreased with restrictive fibrotic lung disease; preserved or improved with effective antifibrotic response.)
Context: Pulmonary function test readout used to measure restrictive ventilatory impairment and treatment response in pulmonary fibrosis.
Pathograph Readouts
Pharmacodynamic Marker Of Architectural distortion and gas-exchange failure Negative Pharmacodynamic
Higher or less-declining FVC indicates less restrictive physiologic impairment from fibrotic architectural distortion; treatment-induced slowing of FVC decline reports pharmacodynamic slowing of disease progression.
Forced vital capacity (FVC)
Traditional Validated Surrogate Endpoint
Patients with pulmonary fibrosis
Show evidence (1 reference)
PMID:24836310 SUPPORT Human Clinical
"In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression;"
The INPULSIS trials link treatment-induced slowing of FVC decline to slowed IPF disease progression.
Show evidence (1 reference)
PMID:24836310 SUPPORT Human Clinical
"The primary end point was the annual rate of decline in forced vital capacity (FVC)."
The pivotal IPF nintedanib trials used annual FVC decline as the primary physiologic endpoint.
{ }

Source YAML

click to show 
name: Idiopathic Pulmonary Fibrosis
creation_date: "2026-04-11T00:00:00Z"
category: Respiratory Disease
parents:
- Respiratory Disease
- Lung Disease
disease_term:
  preferred_term: idiopathic pulmonary fibrosis
  term:
    id: MONDO:0800504
    label: idiopathic pulmonary fibrosis
gene_sets:
- gene_set: MYGENESET:WP_LUNG_FIBROSIS
  relationship: CANONICAL_PATHWAY
  note: >-
    WikiPathways lung fibrosis pathway.
description: >-
  A chronic progressive fibrosing interstitial pneumonia of unknown cause,
  characterized by usual interstitial pneumonia pattern, irreversible loss of
  lung architecture, and worsening respiratory failure.
synonyms:
- IPF
- cryptogenic fibrosing alveolitis
- idiopathic fibrosing alveolitis
progression:
- phase: Progressive fibrotic decline
  notes: Median survival after diagnosis is typically measured in years rather than decades, reflecting relentless physiologic decline.
  evidence:
  - reference: PMID:33965873
    reference_title: "Molecular pathways in idiopathic pulmonary fibrosis pathogenesis: Transcending barriers to optimally targeted pharmacotherapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the survival of patients with idiopathic pulmonary fibrosis
      (IPF) still hovers around a median of two to five years
    explanation: The review summarizes the poor medium-term prognosis that characterizes progressive IPF.
pathophysiology:
- name: Repetitive alveolar epithelial injury and aberrant repair
  description: >-
    Recurrent injury to alveolar epithelial cells, particularly type II
    pneumocytes, initiates a dysregulated wound-healing response that fails to
    restore normal alveolar architecture and instead drives fibrotic remodeling.
  conforms_to: "fibrotic_response#Tissue Injury"
  role: trigger
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: DYSREGULATED
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:35563849
    reference_title: "Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it has been suggested that repeated microinjuries of epithelial cells
      induce a wound healing response, during which fibroblasts differentiate
      into myofibroblasts.
    explanation: This review directly supports repetitive epithelial injury as the initiating trigger for maladaptive wound healing in IPF.
  - reference: PMID:33201251
    reference_title: "Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Apoptosis, senescence, epithelial-mesenchymal transition,
      endothelial-mesenchymal transition, and epithelial cell migration have
      been shown to play a key role in IPF-associated tissue remodeling.
    explanation: This review links epithelial apoptosis and senescence to the abnormal remodeling response after lung injury in IPF.
  downstream:
  - target: AT2 cell senescence and SASP

- name: AT2 cell senescence and SASP
  description: >-
    Recurrent DNA damage and telomere attrition drive alveolar type II
    pneumocytes into a senescent state characterized by a senescence-associated
    secretory phenotype (SASP). An autocrine TGF-beta loop sustains AT2 cell
    senescence while paracrine SASP signals activate lung fibroblasts and
    recruit profibrotic macrophages, converting a transient injury response
    into a self-reinforcing fibrotic program.
  role: amplifier
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  - preferred_term: TGF-beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:37653024
    reference_title: "Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      bleomycin causes DNA damage and activates p53 signaling in AT2-lineage
      cells, leading to AT2-to-AT1 transition-like state with a
      senescence-associated secretory phenotype (SASP). Among SASP-related
      factors, TGF-β plays an exclusive role in promoting lung
      fibroblast-to-myofibroblast differentiation. Moreover, the autocrine
      TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular
      system in non-inflammatory lung fibrogenesis.
    explanation: >-
      Demonstrates that AT2 cell senescence and autocrine TGF-beta feedback
      are mechanistically sufficient to drive fibroblast-to-myofibroblast
      differentiation without immune-cell involvement, establishing AT2
      senescence as a key intermediate between injury and fibrosis.
  - reference: PMID:34813355
    reference_title: "Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recurrent alveolar epithelial cell (AEC) injury may occur in the context
      of predisposing factors (e.g., genetic, environmental, epigenetic,
      immunologic, and gerontologic), leading to metabolic dysfunction,
      senescence, aberrant epithelial cell activation, and dysregulated
      epithelial repair.
    explanation: >-
      Annual Review of Pathology 2022 review places AT2 senescence as a
      consequence of recurrent injury that bridges injury to downstream
      fibrotic mechanisms.
  downstream:
  - target: Profibrotic macrophage recruitment and amplification
  - target: Fibroblast activation and myofibroblast differentiation
  - target: Aberrant basaloid cell emergence

- name: Alveolar epithelial telomere attrition
  conforms_to: "telomere_attrition#Telomere-Initiated DNA Damage and Replicative Senescence"
  description: >-
    In familial and a subset of sporadic IPF, germline mutations in the
    telomerase components TERT and TERC (hTR) and related telomere-maintenance
    genes cause accelerated telomere shortening in alveolar epithelial cells.
    Critically short telomeres in type II pneumocytes provoke a persistent
    DNA-damage response and replicative senescence, linking IPF to the telomere
    biology of the short-telomere syndromes (including dyskeratosis congenita).
  role: trigger
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: telomere maintenance
    term:
      id: GO:0000723
      label: telomere maintenance
    modifier: DECREASED
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  evidence:
  - reference: PMID:17392301
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Germ-line mutations in the genes hTERT and hTR, encoding telomerase
      reverse transcriptase and telomerase RNA, respectively, cause autosomal
      dominant dyskeratosis congenita, a rare hereditary disorder associated
      with premature death from aplastic anemia and pulmonary fibrosis.
    explanation: >-
      Links telomerase (hTERT/hTR) mutations and the short-telomere syndromes to
      pulmonary fibrosis, supporting alveolar telomere attrition as an upstream
      driver in IPF. Evidence source is HUMAN_CLINICAL (familial genetic study).
  - reference: PMID:17392301
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To test the hypothesis that familial idiopathic pulmonary fibrosis may be
      caused by short telomeres, we screened 73 probands from the Vanderbilt
      Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR.
    explanation: >-
      Tests short telomeres as a cause of familial IPF via telomerase-gene
      screening, supporting the telomere-attrition node. Evidence source is
      HUMAN_CLINICAL (familial genetic study).
  downstream:
  - target: AT2 cell senescence and SASP
  - target: AT2 progenitor exhaustion and impaired alveolar regeneration

- name: AT2 progenitor exhaustion and impaired alveolar regeneration
  conforms_to: "stem_cell_exhaustion#Decline in Stem Cell Self-Renewal and Function"
  description: >-
    Alveolar type II pneumocytes are the facultative progenitors that renew the
    alveolar epithelium. Telomere attrition and senescence deplete this
    progenitor pool and limit its self-renewal and regenerative capacity, so
    injured alveoli cannot be properly re-epithelialized; repair is instead
    diverted toward aberrant, profibrotic epithelial states.
  role: effector
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: stem cell population maintenance
    term:
      id: GO:0019827
      label: stem cell population maintenance
    modifier: DECREASED
  - preferred_term: tissue regeneration
    term:
      id: GO:0042246
      label: tissue regeneration
    modifier: DECREASED
  evidence:
  - reference: PMID:18753630
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short telomeres limit tissue renewal capacity in the lung and germ-line
      mutations in telomerase components, hTERT and hTR, underlie inheritance in
      a subset of families with IPF.
    explanation: >-
      Establishes that short telomeres limit lung tissue-renewal capacity,
      supporting exhaustion of the alveolar type II progenitor pool. Evidence
      source is HUMAN_CLINICAL (patient telomere-length study).
  downstream:
  - target: Aberrant basaloid cell emergence

- name: Aberrant basaloid cell emergence
  description: >-
    A subset of AT2 cells under senescent stress fails to differentiate
    normally and instead adopts an aberrant basaloid state marked by KRT17
    expression, epithelial-to-mesenchymal transition markers (COL1A1, FN1),
    senescence markers (p16, p21), and elevated integrin αVβ6 — a potent
    activator of latent TGF-beta. These aberrant basaloid cells are found at
    the epithelial-mesenchymal interface in fibrotic honeycombing and propagate
    a profibrotic secretome that sustains myofibroblast activation and prevents
    restoration of normal alveolar epithelium.
  role: amplifier
  cell_types:
  - preferred_term: aberrant basaloid epithelial cell
    term:
      id: CL:0000646
      label: basal cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    modifier: INCREASED
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  evidence:
  - reference: PMID:33859634
    reference_title: "Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Within both the IPF and SSc-ILD samples we identified a small population
      of the recently described aberrant basaloid cells (or KRT5-/KRT17+
      cells), with no cells sharing this distinct transcriptome amongst the
      control samples
    explanation: >-
      Single-cell RNA sequencing of explanted human IPF lungs identifies
      KRT5-/KRT17+ aberrant basaloid cells exclusively in fibrotic tissue,
      supporting their role as a disease-specific epithelial population at
      the interface of AT2 senescence and myofibroblast activation.
  - reference: PMID:34813355
    reference_title: "Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These studies have uncovered a novel type of AEC with characteristics of
      an aberrant basal cell, which may disrupt normal epithelial repair and
      propagate a profibrotic phenotype.
    explanation: >-
      Annual Review of Pathology 2022 review identifies the aberrant basaloid
      cell population as mechanistically relevant to IPF pathogenesis through
      disruption of normal epithelial repair.
  downstream:
  - target: Fibroblast activation and myofibroblast differentiation

- name: Gut dysbiosis and microbial metabolite dysregulation
  conforms_to: "gut_dysbiosis#Age-Associated Gut Microbiota Alteration"
  description: >-
    Alterations in the composition and function of the gut microbiota drive
    dysbiosis characterized by reduced microbial diversity and decreased
    production of short-chain fatty acids (butyrate, propionate) and secondary
    bile acids. This dysbiosis impairs intestinal epithelial barrier integrity,
    reduces metabolites that support Foxp3+ regulatory T cells and immune
    tolerance, and drives a pro-inflammatory shift in the intestinal immune
    environment. These changes activate innate lymphoid cells and
    mucosal-associated invariant T cells, promoting systemic immune activation
    and increased circulating pro-inflammatory cytokines (TNF-α, IL-6, IL-17)
    that cross the gut-lung barrier to enhance lung fibrotic pathways and amplify
    TGF-beta-mediated fibroblast activation.
  role: amplifier
  locations:
  - preferred_term: large intestine
    term:
      id: UBERON:0000059
      label: large intestine
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
    modifier: DECREASED
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  - preferred_term: innate lymphoid cell
    term:
      id: CL:0001065
      label: innate lymphoid cell
    modifier: INCREASED
  - preferred_term: mucosal-associated invariant T cell
    term:
      id: CL:0000940
      label: mucosal-associated invariant T cell
    modifier: INCREASED
  biological_processes:
  - preferred_term: cell-cell adhesion
    term:
      id: GO:0098609
      label: cell-cell adhesion
    modifier: ABNORMAL
  - preferred_term: short-chain fatty acid metabolic process
    term:
      id: GO:0046459
      label: short-chain fatty acid metabolic process
    modifier: DECREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:42294946
    reference_title: >-
      Potential Roles of Gut Microbiome and Metabolomes in Interstitial Lung
      Disease: Evidence across Preclinical and Clinical Research.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Accumulating evidence supports bidirectional gut-lung axis interactions
      potentially mediated by the microbiota. Alterations in the gut microbiome
      have been associated with the onset and severity of interstitial lung
      disease.
    explanation: >-
      This recent review synthesizes preclinical and clinical evidence linking
      gut dysbiosis to IPF pathogenesis through bidirectional gut-lung axis
      interactions mediated by altered microbiota.
  - reference: PMID:42294946
    reference_title: >-
      Potential Roles of Gut Microbiome and Metabolomes in Interstitial Lung
      Disease: Evidence across Preclinical and Clinical Research.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Preclinical studies demonstrate that gut dysbiosis is associated with
      altered immune responses, increased pro-inflammatory cytokines, and
      enhanced fibrotic pathways, with mechanistic evidence suggesting the
      involvement of specific microbial metabolites (short-chain fatty acids,
      bile acids, and immune mediators.
    explanation: >-
      Preclinical and in vivo evidence demonstrates mechanistic linkages between
      gut dysbiosis and enhanced fibrotic pathways through dysregulated microbial
      metabolites and altered immune responses.
  downstream:
  - target: Profibrotic macrophage recruitment and amplification
  - target: Fibroblast activation and myofibroblast differentiation

- name: Profibrotic macrophage recruitment and amplification
  description: >-
    Injured alveolar units recruit and activate inflammatory and monocyte-derived
    macrophage populations that reinforce a profibrotic repair program and help
    sustain fibroblast activation.
  conforms_to: "fibrotic_response#Inflammatory Recruitment and Amplification"
  role: amplifier
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: INCREASED
  evidence:
  - reference: PMID:32549377
    reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Several lung cell types including alveolar epithelial cells, fibroblasts,
      monocyte-derived macrophages, and endothelial cells have been implicated
      in the development and progression of fibrosis.
    explanation: This review explicitly places monocyte-derived macrophages among the major cell populations driving fibrotic progression in IPF.
  - reference: PMID:38232990
    reference_title: "The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Different cell types (epithelial cells, endothelial cells, fibroblasts
      and macrophages) interact dynamically through multiple signalling
      pathways, including biochemical/molecular and mechanical signals, such as
      stiffness, affecting cell function and differentiation.
    explanation: This review supports dynamic macrophage cross-talk with epithelial and mesenchymal compartments in fibrotic lung disease.
  downstream:
  - target: Fibroblast activation and myofibroblast differentiation

- name: Fibroblast activation and myofibroblast differentiation
  description: >-
    Fibroblasts transition into activated myofibroblasts under the influence of
    TGF-beta signaling and epithelial plasticity programs, creating the central
    effector cell state of established IPF fibrosis.
  conforms_to: "fibrotic_response#Mesenchymal Cell Activation"
  role: central_effector
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: TGF-beta receptor signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  - preferred_term: epithelial to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    modifier: INCREASED
  evidence:
  - reference: PMID:35563849
    reference_title: "Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it has been suggested that repeated microinjuries of epithelial cells
      induce a wound healing response, during which fibroblasts differentiate
      into myofibroblasts.
    explanation: This review directly supports fibroblast-to-myofibroblast differentiation as a core transition downstream of epithelial injury.
  - reference: PMID:32549377
    reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: TGF-β is a critical cytokine that drives development of fibrosis.
    explanation: This review supports TGF-beta signaling as a central profibrotic pathway in IPF.
  - reference: PMID:33201251
    reference_title: "Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Apoptosis, senescence, epithelial-mesenchymal transition,
      endothelial-mesenchymal transition, and epithelial cell migration have
      been shown to play a key role in IPF-associated tissue remodeling.
    explanation: This review supports epithelial-to-mesenchymal transition as part of the abnormal remodeling program in IPF.
  downstream:
  - target: Excessive extracellular matrix deposition

- name: Excessive extracellular matrix deposition
  description: >-
    Activated myofibroblasts deposit excessive extracellular matrix proteins and
    collagen, producing fibroblastic foci, stiffening lung tissue, and locking
    the parenchyma into a self-reinforcing scar state.
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  role: effector
  cell_types:
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:32549377
    reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      changes in gene expression, disrupted glycolysis, and mitochondrial
      oxidation, dysregulated protein folding, and altered phospholipid and
      sphingolipid metabolism result in activation of myofibroblast,
      deposition of extracellular matrix proteins, remodeling of lung
      architecture and fibrosis.
    explanation: This review links activated myofibroblasts directly to ECM deposition, architectural remodeling, and fibrosis in IPF.
  - reference: PMID:38232990
    reference_title: "The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Different cell types (epithelial cells, endothelial cells, fibroblasts
      and macrophages) interact dynamically through multiple signalling
      pathways, including biochemical/molecular and mechanical signals, such as
      stiffness, affecting cell function and differentiation.
    explanation: >-
      Supports the mechano-transduction concept: matrix stiffness signals
      through integrin pathways to maintain fibroblast activation
      independently of soluble TGF-beta, providing a mechanistic basis for
      the feedback edge from ECM deposition back to fibroblast activation.
  downstream:
  - target: Architectural distortion and gas-exchange failure
  - target: Fibroblast activation and myofibroblast differentiation
    description: >-
      Matrix stiffness mechano-transduction (integrin/YAP-TAZ signaling) feeds
      back to maintain fibroblast activation independently of new injury,
      creating a self-sustaining fibrotic loop that persists after the
      initiating injury resolves.

- name: Architectural distortion and gas-exchange failure
  description: >-
    Progressive scarring distorts distal lung units, reduces elastic recoil,
    impairs gas exchange, and culminates in respiratory failure and death.
  conforms_to: "fibrotic_response#Architectural Distortion and Organ Dysfunction"
  role: consequence
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:32549377
    reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The compromised architecture leads to disturbed gas exchange, decreased
      lung compliance, and respiratory failure and death.
    explanation: This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.
phenotypes:
- category: Respiratory
  name: Dyspnea
  description: Persistent exertional breathlessness is the dominant presenting symptom in most patients.
  sequelae:
  - target: Exercise intolerance
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:32274173
    reference_title: "Aerobic and breathing exercises improve dyspnea, exercise capacity and quality of life in idiopathic pulmonary fibrosis patients: systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated
      with significant dyspnea and limited exercise capacity.
    explanation: This systematic review explicitly identifies dyspnea as a major symptomatic burden in IPF.
- category: Respiratory
  name: Exercise intolerance
  description: Progressive loss of ventilatory reserve and gas exchange limits exertional capacity.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:32274173
    reference_title: "Aerobic and breathing exercises improve dyspnea, exercise capacity and quality of life in idiopathic pulmonary fibrosis patients: systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated
      with significant dyspnea and limited exercise capacity.
    explanation: This systematic review explicitly identifies limited exercise capacity as a core functional limitation in IPF.
- category: Respiratory
  name: Respiratory failure
  description: End-stage restrictive lung disease leads to irreversible gas exchange failure.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:32549377
    reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The compromised architecture leads to disturbed gas exchange, decreased
      lung compliance, and respiratory failure and death.
    explanation: This review directly links progressive architectural distortion in IPF to respiratory failure.
biochemical:
- name: Forced Vital Capacity
  presence: Decreased with restrictive fibrotic lung disease; preserved or improved with effective antifibrotic response.
  context: >-
    Pulmonary function test readout used to measure restrictive ventilatory
    impairment and treatment response in pulmonary fibrosis.
  biomarker_term:
    preferred_term: Forced Vital Capacity
    term:
      id: NCIT:C111361
      label: Forced Vital Capacity
  synonyms:
  - FVC
  readouts:
  - target: Architectural distortion and gas-exchange failure
    relationship: PHARMACODYNAMIC_MARKER_OF
    direction: NEGATIVE
    endpoint_context: PHARMACODYNAMIC
    regulatory_endpoint_refs:
    - FDA-SE-adult-noncancer-098
    interpretation: >-
      Higher or less-declining FVC indicates less restrictive physiologic
      impairment from fibrotic architectural distortion; treatment-induced
      slowing of FVC decline reports pharmacodynamic slowing of disease
      progression.
    evidence:
    - reference: PMID:24836310
      reference_title: "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In patients with idiopathic pulmonary fibrosis, nintedanib reduced the
        decline in FVC, which is consistent with a slowing of disease progression;
      explanation: >-
        The INPULSIS trials link treatment-induced slowing of FVC decline to
        slowed IPF disease progression.
  evidence:
  - reference: PMID:24836310
    reference_title: "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary end point was the annual rate of decline in forced vital
      capacity (FVC).
    explanation: >-
      The pivotal IPF nintedanib trials used annual FVC decline as the primary
      physiologic endpoint.
genetic:
- name: MUC5B
  association: Associated
  gene_term:
    preferred_term: MUC5B
    term:
      id: hgnc:7516
      label: MUC5B
  notes: MUC5B is a major susceptibility gene in IPF, and the rs35705950 promoter polymorphism is associated with disease risk and increased pulmonary MUC5B expression.
  evidence:
  - reference: PMID:21506741
    reference_title: "A common MUC5B promoter polymorphism and pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A common polymorphism in the promoter of MUC5B is associated with
      familial interstitial pneumonia and idiopathic pulmonary fibrosis.
    explanation: This human case-control study identifies the MUC5B promoter variant rs35705950 as a major inherited susceptibility factor for IPF.
  - reference: PMID:33965873
    reference_title: "Molecular pathways in idiopathic pulmonary fibrosis pathogenesis: Transcending barriers to optimally targeted pharmacotherapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key among these were the up-regulation of TGFBI, MMP7, TNF, ADAM12,
      activation of immune co-stimulatory markers, toll-like receptors, and
      increased expression of the IPF-related gene MUC5B in both minimal and
      established fibrotic regions of the lungs.
    explanation: This review specifically identifies increased MUC5B expression as part of the molecular program present in fibrotic IPF lung tissue.
- name: TERT
  association: Associated
  gene_term:
    preferred_term: TERT
    term:
      id: hgnc:11730
      label: TERT
  notes: >-
    Monoallelic loss-of-function variants in TERT (telomerase reverse
    transcriptase) cause accelerated telomere shortening in AT2 cells, lowering
    the threshold for senescence induction after injury and driving
    earlier-onset familial pulmonary fibrosis with more rapid disease
    progression.
  evidence:
  - reference: PMID:35078193
    reference_title: "Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC,
      2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2)
    explanation: >-
      Greek national cohort identifies TERT as the most frequently mutated
      telomere-related gene in heritable IPF, establishing its role as a major
      genetic determinant of familial pulmonary fibrosis.
  - reference: PMID:33808277
    reference_title: "Telomeres in Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      More rapidly progressive disease is observed in fibrotic ILD patients
      with telomere gene mutations, regardless of underlying diagnosis.
    explanation: >-
      Review confirms that TERT and other telomere gene mutations confer worse
      prognosis in IPF, consistent with the mechanistic model of AT2 telomere
      dysfunction accelerating senescence.
- name: TERC
  association: Associated
  gene_term:
    preferred_term: TERC
    term:
      id: hgnc:11727
      label: TERC
  notes: >-
    Monoallelic variants in TERC (telomerase RNA component) impair telomerase
    function and shorten telomeres in lung epithelial cells, predisposing to
    familial pulmonary fibrosis via the same AT2 senescence mechanism as TERT
    mutations.
  evidence:
  - reference: PMID:35078193
    reference_title: "Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC,
      2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2)
    explanation: >-
      Greek national cohort identifies TERC as the second most frequently
      mutated telomere-related gene in heritable IPF.
  - reference: PMID:33808277
    reference_title: "Telomeres in Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A number of rare genetic mutations have been identified in genes encoding
      for components of the telomerase complex, including telomerase reverse
      transcriptase (TERT) and telomerase RNA component (TERC), in familial
      and, less frequently, in sporadic fibrotic ILDs.
    explanation: >-
      Review confirms TERC mutations as a cause of familial and sporadic
      fibrotic ILD, consistent with the AT2 telomere shortening to senescence
      mechanistic model.
- name: RTEL1
  association: Associated
  gene_term:
    preferred_term: RTEL1
    term:
      id: hgnc:15888
      label: RTEL1
  notes: >-
    Monoallelic variants in RTEL1 (regulator of telomere elongation helicase 1)
    impair DNA helicase activity at telomeres and have been identified in
    heritable IPF cohorts.
  evidence:
  - reference: PMID:35078193
    reference_title: "Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC,
      2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2)
    explanation: >-
      Greek national cohort identifies RTEL1 as a telomere-related gene
      mutated in heritable IPF, extending the genetic architecture beyond
      TERT/TERC to include DNA helicase function.
treatments:
- name: Pirfenidone
  description: Oral antifibrotic therapy that slows physiologic decline and improves progression-free survival in IPF.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: pirfenidone
      term:
        id: CHEBI:32016
        label: pirfenidone
  evidence:
  - reference: PMID:24836312
    reference_title: "A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pirfenidone, as compared with placebo, reduced disease progression, as
      reflected by lung function, exercise tolerance, and progression-free
      survival, in patients with idiopathic pulmonary fibrosis.
    explanation: The ASCEND phase 3 trial shows pirfenidone slows clinical progression in IPF.
- name: Nintedanib
  description: Antifibrotic tyrosine kinase inhibitor that slows the rate of forced vital capacity decline in IPF.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: nintedanib
      term:
        id: CHEBI:85164
        label: nintedanib
  evidence:
  - reference: PMID:24836310
    reference_title: "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with idiopathic pulmonary fibrosis, nintedanib reduced the
      decline in FVC, which is consistent with a slowing of disease progression
    explanation: The INPULSIS phase 3 trials show nintedanib slows lung function decline in IPF.
- name: Dasatinib and Quercetin (Senolytic Combination)
  description: >-
    A senolytic drug combination targeting senescent cells in IPF. Dasatinib is
    a BCR-ABL/Src kinase inhibitor that clears senescent cells; quercetin is a
    flavonoid with complementary pro-apoptotic effects on senescent cells. Phase
    I pilot trial (NCT02874989) demonstrated feasibility and tolerability in IPF
    patients, supporting the rationale for larger efficacy trials.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dasatinib
      term:
        id: CHEBI:49375
        label: dasatinib (anhydrous)
    - preferred_term: quercetin
      term:
        id: CHEBI:16243
        label: quercetin
  evidence:
  - reference: PMID:36857968
    reference_title: "Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IPF is associated with increased senescent cells burden, which may be
      alleviated with administration of senescent cell targeting drugs termed
      'senolytics'
    explanation: >-
      Phase I pilot trial of the senolytic combination dasatinib + quercetin
      in IPF patients, establishing the rationale that reducing the senescent
      cell burden may slow fibrotic progression.
mechanistic_hypotheses:
- hypothesis_group_id: injury_centric_model
  hypothesis_label: Injury-Centric Wound Healing Model
  status: CANONICAL
  description: >-
    Repetitive alveolar epithelial injury is modeled as the primary upstream
    driver; AT2 cell senescence and subsequent fibroblast activation are
    downstream consequences of failed wound healing. Fibrosis represents an
    aberrant, non-resolving repair response to injury in genetically or
    environmentally susceptible individuals.
  evidence:
  - reference: PMID:35563849
    reference_title: "Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it has been suggested that repeated microinjuries of epithelial cells
      induce a wound healing response, during which fibroblasts differentiate
      into myofibroblasts.
    explanation: >-
      Supports the injury-centric model in which repetitive microinjury is the
      upstream initiating event that leads to fibroblast activation.
  notes: >-
    Retained as CANONICAL because it is consistent with clinical observations
    (cigarette smoke, infections, and micro-aspiration as risk factors) and the
    requirement for repeated injury rather than a single hit. However, this
    model does not fully explain why fibrosis persists and progresses after the
    initiating injury resolves.
- hypothesis_group_id: senescence_first_model
  hypothesis_label: Senescence-First (Stem-Cell Exhaustion) Model
  status: ALTERNATIVE
  description: >-
    Age-related and genetically accelerated AT2 cell telomere attrition renders
    the alveolar epithelium incapable of normal repair; any injury triggers SASP
    rather than regeneration. In this model, IPF is fundamentally a stem-cell
    exhaustion disease in which senescent AT2 cells act as autonomous
    profibrotic drivers through autocrine TGF-beta feedback — even in the
    absence of ongoing immune activation.
  evidence:
  - reference: PMID:37653024
    reference_title: "Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a
      critical cellular system in non-inflammatory lung fibrogenesis.
    explanation: >-
      Demonstrates that AT2 cell senescence and autocrine TGF-beta are
      sufficient for fibrogenesis without immune involvement, consistent with
      the senescence-first model.
  - reference: PMID:33808277
    reference_title: "Telomeres in Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Loss of regenerative potential of alveolar type II epithelial cells
      (AT2) cells following injury has been postulated to underlie
      telomeropathy-associated lung fibrosis, with concomitant excessive
      proliferation of airway cells displaying abnormal phenotypes
    explanation: >-
      Review describes telomere-driven loss of AT2 regenerative capacity as a
      mechanistic explanation for the strong age and telomere-length
      associations in IPF.
  notes: >-
    Supported by the exponential age-dependence of IPF, by telomere gene
    mutations in familial IPF causing earlier onset, and by the Enomoto 2023
    organoid model showing immune-independent fibrogenesis. However, this model
    alone does not explain why fibrosis is patchy or why some individuals with
    short telomeres do not develop IPF without injury.
- hypothesis_group_id: feedback_loop_convergence_model
  hypothesis_label: Convergent Self-Sustaining Feedback Loop Model
  status: ALTERNATIVE
  description: >-
    The injury-centric and senescence-first models converge once AT2 senescence
    and matrix stiffness feedback are engaged. Neither entry point alone is
    sufficient; the system becomes self-sustaining through: the autocrine AT2
    SASP TGF-beta loop that perpetuates senescence; matrix stiffness
    mechano-transduction (integrin/YAP-TAZ) that maintains fibroblast
    activation independently of new injury; and aberrant basaloid cell
    accumulation that prevents restoration of normal alveolar epithelium.
    Therapeutic intervention must target these feedback loops, not just the
    initiating injury, to halt progression.
  evidence:
  - reference: PMID:34813355
    reference_title: "Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a
      complex interplay of cell types and signaling pathways. Recurrent
      alveolar epithelial cell (AEC) injury may occur in the context of
      predisposing factors (e.g., genetic, environmental, epigenetic,
      immunologic, and gerontologic), leading to metabolic dysfunction,
      senescence, aberrant epithelial cell activation, and dysregulated
      epithelial repair.
    explanation: >-
      Annual Review of Pathology review frames IPF as a convergence of
      multiple predisposing factors and cell types, consistent with the
      feedback loop model in which no single upstream event fully explains
      the disease.
  notes: >-
    Emerging as the dominant synthesis view as single-cell and organoid data
    accumulate. This model explains progressive disease despite removal of
    injury trigger, age-dependence without universal penetrance, and why
    neither anti-inflammatory nor single-pathway treatments have substantially
    changed long-term outcomes.
discussions:
- discussion_id: disc_ipf_injury_vs_senescence_ordering
  prompt: >-
    Is repetitive alveolar epithelial injury the primary upstream driver of IPF,
    or does age-related AT2 cell senescence and telomere attrition precede and
    predispose to fibrosis independently of ongoing injury?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#AT2 cell senescence and SASP
  rationale: >-
    The causal ordering among epithelial injury, AT2 cell senescence, and
    fibroblast activation remains unresolved. In the injury-centric model,
    repetitive microinjury is the upstream event and senescence is a downstream
    consequence, implying that removing the injury source should be sufficient
    to halt progression. In the senescence-first model, age-related and genetic
    telomere attrition renders AT2 cells intrinsically unable to regenerate, so
    any injury triggers SASP rather than repair. The Enomoto 2023 organoid model
    (PMID:37653024) provides the strongest mechanistic evidence that AT2
    senescence drives fibrogenesis non-inflammatorily, but it uses bleomycin as
    the initial stimulus, leaving open whether senescence can initiate fibrosis
    in the complete absence of an exogenous trigger. Clinical observations that
    IPF can progress in the absence of identified ongoing exposure support the
    senescence-first or feedback-loop models over a purely injury-dependent
    explanation.
- discussion_id: disc_ipf_ecm_feedback_irreversibility
  prompt: >-
    What are the critical feedback loops — autocrine AT2 SASP, matrix
    stiffness mechano-transduction, and aberrant basaloid cell accumulation —
    that make IPF fibrosis self-sustaining and progressive after the initiating
    injury resolves, and which of these is most therapeutically tractable?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Excessive extracellular matrix deposition
  - pathophysiology#Aberrant basaloid cell emergence
  rationale: >-
    Multiple positive feedback loops have been proposed to explain why IPF
    progresses even after the putative initiating injury resolves: the autocrine
    AT2 SASP TGF-beta loop (PMID:37653024); matrix stiffness
    mechano-transduction via integrin/YAP-TAZ that maintains fibroblast
    activation independently of soluble TGF-beta; and aberrant basaloid cell
    accumulation that depletes the normal AT2 stem cell pool and prevents
    alveolar re-epithelialization. The relative contribution of each loop to
    disease progression has not been established in humans. Existing approved
    therapies (pirfenidone and nintedanib) slow progression but do not stop or
    reverse fibrosis, suggesting these feedback loops are not adequately
    targeted. Senolytics (dasatinib + quercetin, PMID:36857968) are being
    evaluated as a strategy to interrupt the AT2 SASP feedback loop, but
    phase III efficacy data are lacking.
- discussion_id: disc_ipf_gut_lung_axis_causality
  prompt: >-
    Does gut dysbiosis drive IPF progression (dysbiosis → fibrosis), or is it
    a secondary consequence of systemic inflammation and drug effects in
    established IPF (fibrosis → dysbiosis)? Are microbial metabolite deficits
    (SCFA, secondary bile acids) individually sufficient to amplify pulmonary
    fibrosis, or do they require cofactors? Can fecal microbiota transplantation
    attenuate pulmonary inflammation in human ILD?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Gut dysbiosis and microbial metabolite dysregulation
  rationale: >-
    Current evidence for gut-lung axis involvement in IPF is primarily from
    associative cross-sectional studies and preclinical bleomycin models
    (PMID:42294946). The directionality of the gut-lung axis relationship has
    not been established: dysbiosis may be upstream (amplifying fibrosis via
    pro-inflammatory cytokines and reduced immune tolerance) or downstream
    (resulting from systemic inflammation, malnutrition, or IPF medications
    such as nintedanib and pirfenidone that alter gut microbiota). Metabolite
    sufficiency experiments (butyrate or propionate supplementation in IPF
    models) are limited. Interventional FMT studies in animal models suggest
    attenuation of pulmonary inflammation, but no human clinical evidence
    exists. Establishing causality and metabolite specificity is required before
    gut-lung axis modulation can be considered a therapeutic target in IPF.
  proposed_experiments:
  - experiment_id: exp_ipf_microbiome_temporal_cohort
    name: Longitudinal microbiome profiling in IPF cohorts
    description: >-
      Longitudinal microbiome profiling in prospective IPF cohorts with
      time-matched lung function decline to assess whether dysbiosis precedes
      or follows functional deterioration, establishing causal directionality.
  - experiment_id: exp_ipf_germ_free_bleomycin
    name: Germ-free and antibiotic-depleted mouse IPF models
    description: >-
      Germ-free or antibiotic-depleted mouse bleomycin models to test whether
      microbiota depletion attenuates pulmonary fibrosis, establishing a
      causal contribution of gut microbiota to lung fibrotic pathways.
  - experiment_id: exp_ipf_scfa_supplementation
    name: SCFA supplementation in IPF mouse models
    description: >-
      SCFA (butyrate and propionate) supplementation in bleomycin-induced
      pulmonary fibrosis mouse models to determine whether restoring microbial
      metabolite levels reduces fibrotic burden and pro-inflammatory cytokines.
📚

References & Deep Research

Deep Research

1
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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Idiopathic Pulmonary Fibrosis. Core disease mechanisms, molecular and cell...
Asta Scientific Corpus Retrieval 18 citations 2026-04-11T11:19:01.686115

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Idiopathic Pulmonary Fibrosis. Core disease mechanisms, molecular and cell...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] Comorbidity of Pulmonary Fibrosis and COPD/Emphysema: Research Status, Trends, and Future Directions --------- A Bibliometric Analysis from 2004 to 2023

  • Authors: H. Fang, Tairan Dong, Zhuojun Han, Shanlin Li, Mingfei Liu et al.
  • Year: 2023
  • Venue: International Journal of Chronic Obstructive Pulmonary Disease
  • URL: https://www.semanticscholar.org/paper/e9e39dadd7fb76d988cbc101b957517276f55d7f
  • DOI: 10.2147/COPD.S426763
  • PMID: 37720874
  • PMCID: 10505036
  • Citations: 4
  • Summary: The research hotspots and trends identified in this study provide a reference for in-depth research in this field, aiming to promote the development of the comorbidity of pulmonary fibrosis and COPD/emphysema.
  • Evidence snippets:
  • Snippet 1 (score: 0.701) > Cluster #0 explores clinical conditions associated with pulmonary fibrosis, including idiopathic interstitial pneumonia, idiopathic fibrosis, and pulmonary fibrosis combined with emphysema. This cluster establishes more precise classification and diagnostic criteria for these conditions, distinguishing them from one another, and emphasizes the necessity of actively pursuing accurate diagnosis and treatment strategies in clinical research. 1][22][23] Cluster #1 primarily focuses on the latest clinical research concerning idiopathic pulmonary fibrosis, encompassing clinical classification, diagnostic criteria, cutting-edge methodologies, the influence of comorbidities on disease progression, and the effectiveness of various drug treatment modalities. ][26][27] The following clusters are dedicated to studying the pathogenesis of related diseases, including idiopathic fibrosis, by investigating genes, signaling pathways, cellular mechanisms, and more. Cluster #2 focuses on elucidating the mechanisms of cellular senescence in idiopathic fibrosis. Lung senescence, characterized by an increased number of senescent cells, is believed to directly contribute to various age-related respiratory diseases. Targeting cellular senescence through therapeutic interventions could potentially delay or even reverse age-related respiratory diseases. 9][30] Cluster #3 primarily engages in fundamental research on the cellular and molecular mechanisms underlying pulmonary fibrosis. It investigates related genes, regulatory factors, and cellular pathways to gain a deeper understanding of the pathogenic mechanisms of this disease. ][33][34] Cluster #7 delves into the intricate cellular and molecular mechanisms underlying pulmonary fibrosis. It focuses on tissue remodeling, structural alterations in fibrotic lesions, and aberrant cell populations. 6][37][38] Cluster #8 explores the cellular and molecular mechanisms of lung tissue and their implications for treatments. It demonstrates that age-related lung diseases share common mechanisms, such as telomere shortening, abnormal tissue remodeling, and functional damage. 0][41] Cluster #9 investigates the crucial role of Redox regulatory proteins, oxidative stress, and inflammatory response in the pathogenesis of pulmonary diseases, including pulmonary fibrosis.

[2] The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery

  • Authors: Emanuel Kolanko, Anna Cargnoni, Andrea Papait, A. Silini, P. Czekaj et al.
  • Year: 2024
  • Venue: European Respiratory Review
  • URL: https://www.semanticscholar.org/paper/b4406eb865ebf9edad815c6b363dbb5ace4f8679
  • DOI: 10.1183/16000617.0127-2023
  • PMID: 38232990
  • PMCID: 10792439
  • Citations: 32
  • Summary: In vitro lung fibrosis models have progressively improved to represent tools closely mimicking pathological processes and allow advancements of personalised medicine and enhance comprehension of pathogenic molecular mechanisms.
  • Evidence snippets:
  • Snippet 1 (score: 0.550) > Lung fibrosis is a complex process, with unknown underlying mechanisms, involving various triggers, diseases and stimuli. Different cell types (epithelial cells, endothelial cells, fibroblasts and macrophages) interact dynamically through multiple signalling pathways, including biochemical/molecular and mechanical signals, such as stiffness, affecting cell function and differentiation. Idiopathic pulmonary fibrosis (IPF) is the most common fibrosing interstitial lung disease (fILD), characterised by a notably high mortality. Unfortunately, effective treatments for advanced fILD, and especially IPF and non-IPF progressive fibrosing phenotype ILD, are still lacking. The development of pharmacological therapies faces challenges due to limited knowledge of fibrosis pathogenesis and the absence of pre-clinical models accurately representing the complex features of the disease. To address these challenges, new model systems have been developed to enhance the translatability of preclinical drug testing and bridge the gap to human clinical trials. The use of two- and three-dimensional in vitro cultures derived from healthy or diseased individuals allows for a better understanding of the underlying mechanisms responsible for lung fibrosis. Additionally, microfluidics systems, which replicate the respiratory system's physiology ex vivo, offer promising opportunities for the development of effective therapies, especially for IPF. Tweetable abstract In vitro lung fibrosis models have progressively improved to represent tools closely mimicking pathological processes and allow advancements of personalised medicine and enhance comprehension of pathogenic molecular mechanisms. https://bit.ly/40P8gqw
  • Snippet 2 (score: 0.510) > Additionally, there are transgenic models in which specific gene mutations associated with ILD, such as a mutant surfactant protein C gene (SFTPC) in alveolar type II (AT2) cells [16], are triggered to induce the development of pulmonary fibrosis. In addition, the bleomycin-induced pulmonary fibrosis model is widely used and well characterised [17]. This model has proven valuable in the exploration of novel pathogenic mechanisms that may have relevance to human disease. Notably, recent research has demonstrated the pivotal role of RNA-binding motif protein 7 (RBM7) in fibrosis onset [18]. Nevertheless, these models present notable limitations [19], possibly for the fact that all animal models of IPF are artificially induced using single agents or target a single cell type, while it is well known that the pathogenesis is multifactorial and still remains elusive. > In this context, in vitro models, despite being a simplified representation of actual diseased tissue, can be valuable because they allow for the identification of specific cellular and molecular mechanisms that trigger and induce disease progression. > Nonetheless, as they continue to evolve, in vitro models are increasingly approaching the complexity of in vivo systems. For example, lung organoids derived from induced pluripotent stem cells (iPSCs) obtained from patients enable monitoring of the alterations acquired by the different cell populations during the disease progression. This approach aids in pinpointing the specific states of maturation where issues may arise. Moreover, the use of human material, with a personalised medicine perspective, enables the screening of drugs, including off-label drugs, for drug repurposing. In recent years, in vitro models have been developed to improve preclinical drug testing and bridge the translational gap to human clinical trials. These techniques offer advanced imaging and analysis of disease mechanisms, allowing for drug discovery and validation in a personalised manner (figure 2 and table 1). This is a comprehensive overview of the various in vitro models that are accessible for studying the molecular mechanisms underlying fibrosis pathogenesis, as well as their applications in drug screening.

[3] Cellular Senescence in Lung Fibrosis

  • Authors: Fernanda Hernández-González, R. Faner, M. Rojas, A. Agustí, M. Serrano et al.
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/072814da23bd69a06a991e6dce8d86d029925578
  • DOI: 10.3390/ijms22137012
  • PMID: 34209809
  • PMCID: 8267738
  • Citations: 61
  • Influential citations: 1
  • Summary: Current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence are highlighted, and the idea that it also drives degenerative processes such as lung fibrosis is strengthened.
  • Evidence snippets:
  • Snippet 1 (score: 0.549) > For several decades, understanding lung fibrosis as a process that limits lifespan has challenged scientists. Progressive loss of lung function due to pulmonary fibrosis contributes significantly to the ever-increasing burden of chronic disease throughout the world. Around half of deaths in the developed world are attributable to fibrotic diseases, including idiopathic pulmonary fibrosis (IPF), the most common fibrotic interstitial lung disease (ILD) characterized by progressive and irreversible respiratory failure and death [1,2]. The phenomenological complexity existing in the lung fibrosis process has led, over the years, to a rising number of hypotheses about the specific cellular and molecular causes. The most prominent feature of lung fibrosis is a gradual age-related loss of function that occurs at the molecular, cellular, and tissue levels. The lack of somatic maintenance and repair functions and the stochastic enforcement of damage may explain the marked variability of cellular mechanisms that appear to be involved in aging phenotypes, such as lung fibrosis [3,4]. > Fibrosis and wound healing are essentially interwoven processes, driven by a cascade of injury, inflammation, fibroblast proliferation and migration, matrix deposition and remodelling. Pathological fibrogenesis that occurs in many diverse organs and diseases is a dynamic process involving complex interactions between epithelial cells, fibroblasts, immune cells (macrophages, T-cells), and/or endothelial injuries [5,6]. There are many extrinsic hazards known to induce injury to lung epithelium-infections, exposures to organic or inorganic components, cigarette smoking, and so forth-while there is also damage of unknown aetiology. As a response to lung injury, many interrelated woundhealing pathways are activated in order to facilitate the repair, turnover, and adaptation of lung tissue [7]. However, although their aetiology and causative mechanisms varies, the different fibrotic lung diseases all fail to properly eliminate inciting factors, leading to continued tissue damaging with an abnormal and exaggerated accumulation of extracellular matrix (ECM) components and collagen deposition.

[4] Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

  • Authors: T. Phan, P. Paliogiannis, Gheyath K Nasrallah, Roberta Giordo, A. Eid et al.
  • Year: 2020
  • Venue: Cellular and Molecular Life Sciences: CMLS
  • URL: https://www.semanticscholar.org/paper/60ab2fce378cefe715daabd6fdd84f8a31c65c7a
  • DOI: 10.1007/s00018-020-03693-7
  • PMID: 33201251
  • PMCID: 7669490
  • Citations: 269
  • Influential citations: 9
  • Summary: An update is provided regarding the emerging cellular and molecular mechanisms involved in the onset and progression of idiopathic pulmonary fibrosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.548) > Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is a progressive, irreversible, and typically lethal disease characterized by an abnormal fibrotic response involving vast areas of the lungs. Given the poor knowledge of the mechanisms underpinning IPF onset and progression, a better understanding of the cellular processes and molecular pathways involved is essential for the development of effective therapies, currently lacking. Besides a number of established IPF-associated risk factors, such as cigarette smoking, environmental factors, comorbidities, and viral infections, several other processes have been linked with this devastating disease. Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling. Moreover, molecules, such as chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, non-coding RNAs, and cellular processes including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, hypoxia, and alternative polyadenylation have been linked with IPF development. Importantly, strategies targeting these processes have been investigated to modulate abnormal cellular phenotypes and maintain tissue homeostasis in the lung. This review provides an update regarding the emerging cellular and molecular mechanisms involved in the onset and progression of IPF.
  • Snippet 2 (score: 0.530) > Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is an irreversibly progressive and usually lethal disease. IPF patients typically succumb to respiratory failure secondary to loss of respiratory function from extensive fibrotic scarring of the lung parenchyma. Following diagnosis, the average life expectancy is 3-5 years. IPF is more common in males and individuals older than 60 years. The histopathological hallmarks include subpleural fibrosis, subepithelial fibroblastic foci, and microscopic honeycombing [1][2][3][4]. The clinical progress is usually complicated by acute episodes of respiratory function deterioration, termed IPF exacerbations. No effective treatments are available in preventing and controlling the acute exacerbations of IPF [5,6]. The most common complications of IPF include lung cancer, depression, pulmonary hypertension, muscle weakness, heart failure, thrombosis, acute respiratory distress syndrome (ARDS), and respiratory failure. The recent introduction of two anti-fibrotic drugs, pirfenidone and nintedanib, will likely lead to a significant retardation in lung-function decline and a reduction in the incidence and severity of associated complications. However, as these agents are not curative, new therapeutic approaches are needed [7] Given that the exact pathophysiological mechanisms involved in IPF remain elusive. Additional studies on the cellular processes and molecular pathways involved are essential for the development of effective IPF therapies. A number of processes and factors, such as the role of aging and cellular apoptosis, oxidative stress, endoplasmic reticulum stress, cellular plasticity, and noncoding RNAs are the focus of intense research. Their better understanding might lead to the effective modulation of aberrant cellular processes and the maintenance of tissue homeostasis in the lung. This review discusses the key evolving concepts in IPF pathogenesis, the cellular and molecular mechanisms involved in the onset and progression of the disease, and the identification and development of novel targeted therapies.

[5] Targeting Chitinase 1 and Chitinase 3-Like 1 as Novel Therapeutic Strategy of Pulmonary Fibrosis

  • Authors: S. Lee, Chang-min Lee, B. Ma, Suchitra Kamle, J. Elias et al.
  • Year: 2022
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/8cc7e64fb666492633849749ee3952faf632dac9
  • DOI: 10.3389/fphar.2022.826471
  • PMID: 35370755
  • PMCID: 8969576
  • Citations: 20
  • Summary: Specific roles and regulatory mechanisms of CHIT1 and CHI3L1 in profibrotic cell and tissue responses as novel therapeutic targets of pulmonary fibrosis are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.541) > Tissue fibrosis is a major cause of morbidity in pulmonary fibrosis. As a normal repair response, fibrosis is a series of process of cellular damage caused by various conditions that initiate inflammation, recruitments of inflammatory cells, followed by final tissue repair and termination of inflammation. Loss of regulatory signals and imbalance in the process of wound healing leads to aberrant activation of repair response, causing pathologic fibrosis in various organs including lung, resulting in a disease state (Wilson and Wynn, 2009). Since excellent review articles detailing the molecules and signaling pathways involved in the pathogenesis of pulmonary fibrosis are already available (Micallef et al., 2012;Wolters et al., 2014;Sgalla et al., 2018;Strykowski and Adegunsoye, 2021), in this section, we only focus on the discussion of major factors leading to pathologic fibrosis, that can be also regulated by CHIT1 or CHI3L1 in the development and progression of pulmonary fibrosis. Pulmonary fibrosis comprises a number of different etiologies and pathologies with completely different clinical features and therapeutic responses. Accordingly, there are significant limitations in identifying common pathogenetic mechanisms of pulmonary fibrosis. This is particularly true for in vitro cell or in vivo preclinical animal models of pulmonary fibrosis, since currently no preclinical models are exactly representing the characteristic cellular and tissue responses of IPF and other interstitial lung disease (ILD). In addition, so far relatively small number of human studies with dysregulated expression of CHIT1 and/or CHI3L1 in the patients with IPF and ILD add certain limitations in direct clinical translation of preclinical data. With these limitations in mind, here the molecular and mechanistic implications of CHIT1 and CHI3L1 as potential therapeutic targets are discussed based on up-to-dated and common lung pathologies of pulmonary fibrosis.

[6] Cellular and Molecular Genetic Mechanisms of Lung Fibrosis Development and the Role of Vitamin D: A Review

  • Authors: Darya Enzel, M. Kriventsov, T. Sataieva, V. Malygina
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/fc44de05d17a984b1918bf7d7db585d16b6dc7dd
  • DOI: 10.3390/ijms25168946
  • PMID: 39201632
  • PMCID: 11355055
  • Citations: 6
  • Summary: This literature review presents the key modern concepts concerning molecular genetics and cellular mechanisms of lung fibrosis development, based mainly on in vitro and in vivo studies in experimental models of bleomycin-induced pulmonary fibrosis, as well as the latest data on metabolic features, potential targets, and effects of vitamin D and its metabolites.
  • Evidence snippets:
  • Snippet 1 (score: 0.526) > Idiopathic pulmonary fibrosis remains a relevant problem of the healthcare system with an unfavorable prognosis for patients due to progressive fibrous remodeling of the pulmonary parenchyma. Starting with the damage of the epithelial lining of alveoli, pulmonary fibrosis is implemented through a cascade of complex mechanisms, the crucial of which is the TGF-β/SMAD-mediated pathway, involving various cell populations. Considering that a number of the available drugs (pirfenidone and nintedanib) have only limited effectiveness in slowing the progression of fibrosis, the search and justification of new approaches aimed at regulating the immune response, cellular aging processes, programmed cell death, and transdifferentiation of cell populations remains relevant. This literature review presents the key modern concepts concerning molecular genetics and cellular mechanisms of lung fibrosis development, based mainly on in vitro and in vivo studies in experimental models of bleomycin-induced pulmonary fibrosis, as well as the latest data on metabolic features, potential targets, and effects of vitamin D and its metabolites.

[7] Translational control of the fibroblast-extracellular matrix association

  • Authors: R. Nho, V. Polunovsky
  • Year: 2013
  • Venue: Translation
  • URL: https://www.semanticscholar.org/paper/9761d71436d581f1a9fae8de80d2a797b79bf162
  • DOI: 10.4161/trla.23934
  • PMID: 26824013
  • PMCID: 4718055
  • Citations: 10
  • Summary: Evidence is presented indicating that the dysregulation of the eIF4F-mediated translational apparatus is an important factor in the development and progression of IPF and other fibrotic disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.524) > Pulmonary fibrosis can be a complication of a group of lung disorders called interstitial lung diseases (ILDs). 1 In cases when pulmonary fibrosis develops within the lung in the absence of any known provocations, it is termed idiopathic pulmonary fibrosis (IPF), which is also known as cryptogenic fibrosing alveolitis (CFA). IPF is characterized by abnormal expansion of granulation tissue due to excessive production of ECM, hyperpropagation of stromal fibroblasts and vast scarring of normal lung parenchyma leading to a deficiency in gas exchange. IPF is usually fatal with life expectance within 2 to 6 y following diagnosis. 2 Although there has been some progress in understanding the pathogenesis of IPF, there is still no proven effective therapy Pulmonary fibrosis is a severe lung disease characterized by sustained propagation of lung fibroblasts and relentless accumulation of extracellular matrix (ECM). Idiopathic pulmonary fibrosis (IPF) is the most severe chronic form of pulmonary fibrosis and results both in the gradual exchange of normal lung parenchyma with fibrotic tissue and in the irreversible impairment of gas exchange in the lung. Despite the urgency for novel therapies in IPF treatment, there is no effective and proven medical therapy available. Molecular mechanisms underlying IPF pathogenesis include aberrant ECM signaling through the canonical integrin/PI3K/Akt/ mTORC1 signal transduction pathway. One important and well-characterized downstream effector of this pathway is the cellular protein synthesis machinery. Here we will review the recent advances in our understanding of the function of ECM and integrin receptor signaling in development of IPF and will present evidence indicating that the dysregulation of the eIF4F-mediated translational apparatus is an important factor in the development and progression of IPF and other fibrotic disorders. We further discuss the perspectives and challenges to curbing this deadly disease by targeting aberrant translation. > available and lung transplantation is the only viable intervention in end-stage disease.

[8] Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

  • Authors: V. Suryadevara, R. Ramchandran, D. Kamp, V. Natarajan
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/9ad48e612a124c8c4940043f4bae96946d26afc7
  • DOI: 10.3390/ijms21124257
  • PMID: 32549377
  • PMCID: 7352853
  • Citations: 108
  • Influential citations: 5
  • Summary: The current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipid metabolism and their metabolizing enzymes in the development of lung fibrosis is described.
  • Evidence snippets:
  • Snippet 1 (score: 0.523) > Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF.

[9] Molecular pathways in idiopathic pulmonary fibrosis pathogenesis: Transcending barriers to optimally targeted pharmacotherapies

  • Authors: R. Strykowski, A. Adegunsoye
  • Year: 2021
  • Venue: EBioMedicine
  • URL: https://www.semanticscholar.org/paper/3f70120771654984a132710d119c3cee6849ff0b
  • DOI: 10.1016/j.ebiom.2021.103373
  • PMID: 33965873
  • PMCID: 8114113
  • Citations: 1
  • Summary: An array of mechanisms involved in the pathophysiologic progression of previously normal lung tissue to fibrosis in IPF are examined, linking the molecular and cellular events associated with this complex disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.519) > Although the survival of patients with idiopathic pulmonary fibrosis (IPF) still hovers around a median of two to five years, [1] the therapeutic landscape of this devastating interstitial lung disease is encumbered by a paucity of effective pharmacotherapies. Widely used anti-fibrotic medications slow the rate of functional decline [2,3] but are often associated with adverse effects and persistently high symptom burden. As the pathophysiologic mechanisms underlying fibrosis are yet to be fully elucidated, our understanding of disease progression in IPF remains stifled, posing substantial limitations to the potential value that could be gained from more novel therapies targeting these mechanisms. Prior genome-wide associated studies evaluating the genetic profiles of affected patients have identified several notable variants and risk polymorphisms associated with IPF pathogenesis. [4] Likewise, recent epigenomic, transcriptomic, and proteomic data have helped to generate a single-cell atlas of IPF defining key molecular factors and pathways in the progression of fibrosis. [5] Other histopathologic analyses and investigations focused on immunophenotyping have identified phenotypically distinct CD4 + T cell infiltrates within the lung tissue in patients with IPF. [6] From a macroscopic perspective, recent investigations have found a significant loss of terminal bronchioles in lung tissue obtained from patients with IPF, implicating the small airways in this disease. [7] Taken together, these underscore numerous efforts that further illuminate the pathophysiology of this complex disease, with the overall goal of identifying optimal therapeutic targets and improving currently existing ones. > In this issue of EBioMedicine, Xu and colleagues [8] examine an array of mechanisms involved in the pathophysiologic progression of previously normal lung tissue to fibrosis in IPF. [8] Their novel and exciting findings link the molecular and cellular events associated with IPF to the concomitant structural and histological events.

[10] Bleomycin-Induced Fibrosis and the Effectiveness of Centella Asiatica as a Treatment

  • Authors: N. Soeroso, M. Ichwan, A. S. Wahyuni, C. Mariedina, Yabestin Pakpahan
  • Year: 2024
  • Venue: Journal of Experimental Pharmacology
  • URL: https://www.semanticscholar.org/paper/d54d6d4e0d4a082eaac34ebd0bc406fdd20850ca
  • DOI: 10.2147/JEP.S463899
  • PMID: 39345799
  • PMCID: 11438459
  • Citations: 3
  • Summary: The induction of bleomycin 4 mg/kg/BB was proven to cause fibrosis in the lungs of rats, and Centella asiatica extract was used as a treatment and further research regarding antifibrotic drugs is hoped to reduce fibrotic areas significantly.
  • Evidence snippets:
  • Snippet 1 (score: 0.517) > Fibrosis is the most common interstitial lung disease defined by regular interstitial pneumonia histological pattern. 1 Idiopathic pulmonary fibrosis is a lung disorder where scar tissue is found in the lungs, however, the cause is still unknown. Pulmonary fibrosis patients may have a poor prognosis compared to other malignancies. Untreated pulmonary fibrosis can progress to CPD (Chronic Lung Disease), resulting in tissue death. 2 Data on the incidence of pulmonary fibrosis varies, in the United States, it is 6.8-8.8 per 100,000 population per year, Europe 0.22-7.4 per 10,000 population, and the incidence of fibrosis increases with age. 3,4 leomycin is a compound produced by Streptomyces verticillus bacteria, and the bacteria is often used in trial animal interventions. Bleomycin is often used in chemotherapy, but this compound has the side effect of being toxic to lung cells. The mechanism of bleomycin toxicity has been tested in vitro. Side effects of using bleomycin include nausea, fever, vomiting, and allergies. Treatment with bleomycin can also cause interstitial pneumonitis and pulmonary fibrosis. 5 nimal models are crucial to the study of disease, and lung pathobiology is studied using many different models. Over time, numerous models of pulmonary fibrosis have been created. Common techniques include silica or asbestos, radiation damage, bleomycin, transgenic mice, and gene transfer via fibrogenic cytokines. As of right now, bleomycin is the mechanism employed to cause experimental lung fibrosis in animals. 6 egrettably, lung damage resulting from pulmonary fibrosis is irreversible and permanent. The lungs may function better if the condition is identified early and treated. The majority of pulmonary fibrosis therapies aim to enhance quality of life and reduce symptoms. Lung illness fibroproliferative is common and has a high death rate. Inflammation, mesenchymal cell proliferation, and the deposition of interstitial matrix constituents including collagen and fibronectin are all involved in the pathophysiology of fibrotic lung disease.

[11] Lung regeneration: diverse cell types and the therapeutic potential

  • Authors: Yutian Chen, Zhen Li, Gaili Ji, Shaochi Wang, Chunheng Mo et al.
  • Year: 2024
  • Venue: MedComm
  • URL: https://www.semanticscholar.org/paper/0fbe00de4b129b66ffcc63fd4298d45dc0352a8c
  • DOI: 10.1002/mco2.494
  • PMID: 38405059
  • PMCID: 10885188
  • Citations: 27
  • Summary: A review of the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.
  • Evidence snippets:
  • Snippet 1 (score: 0.512) > Abstract Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

[12] The Mechanism of Oxidative Stress in Pulmonary Fibrosis and Research Progress

  • Authors: Duo Xu, Qian Wang, Meng Lyu, Chunyu Huang, Xianglin Yuan et al.
  • Year: 2026
  • Venue: Antioxidants
  • URL: https://www.semanticscholar.org/paper/54c6c9cba7e158d270ee82da0a58117282c8ae40
  • DOI: 10.3390/antiox15010142
  • PMID: 41596200
  • PMCID: 12837592
  • Citations: 1
  • Summary: This review summarizes the regulatory mechanisms of oxidative stress in pulmonary fibrosis, with a focus on its critical role in inducing and promoting fibrosis through relevant target cells and signaling pathways.
  • Evidence snippets:
  • Snippet 1 (score: 0.511) > Pulmonary fibrosis (PF) is a group of chronic progressive lung diseases characterized by irreversible remodeling of lung tissue structure, abnormal proliferation of fibroblasts, and excessive deposition of extracellular matrix (ECM), among which idiopathic pulmonary fibrosis (IPF) is the most typical subtype. Currently, the only two clinically approved therapeutic drugs (nintedanib and pirfenidone) can only partially slow disease progression without reversing fibrotic lesions, and are associated with varying degrees of adverse effects. Oxidative stress, defined as a pathological imbalance between systemic oxidant and antioxidant systems, has been substantiated by extensive research as a pivotal mechanism driving the pathogenesis and progression of pulmonary fibrosis. This review summarizes the regulatory mechanisms of oxidative stress in pulmonary fibrosis, with a focus on its critical role in inducing and promoting fibrosis through relevant target cells and signaling pathways. We also specifically highlight the latest progress and challenges in therapeutic strategies targeting oxidative stress, and discuss next-generation therapies, including the modulation of endogenous antioxidant pathways, supplementation of exogenous antioxidants, as well as nanomaterials, exosomes, and combination therapies. We hope this review will deepen the understanding of oxidative stress and pulmonary fibrosis, and provide new directions for improving the clinical efficacy of oxidative stress-targeted therapies.

[13] Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis

  • Authors: I. Chen, Yi-Ching Liu, Yen-Hsien Wu, S. Lo, Z. Dai et al.
  • Year: 2022
  • Venue: Cells
  • URL: https://www.semanticscholar.org/paper/1254ef188f65fe4aacc0fbc21eb4ea91c5256fba
  • DOI: 10.3390/cells11091543
  • PMID: 35563849
  • PMCID: 9099509
  • Citations: 12
  • Summary: This review summarizes the current research on proteasome inhibitors for pulmonary fibrosis, and provides a reference for whether proteasomal inhibition have the potential to become new drugs for the treatment of lung fibrosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.510) > Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and usually lethal disease characterized by an abnormal fibrotic response involving large areas of the lungs. Risk factors associated with IPF include smoking, environmental factors, comorbidities, and viral infections [1]. Most patients have persistent dyspnea and limited exercise tolerance resulting in a poor quality of life. Many patients develop pulmonary hypertension and are at an increased risk of pulmonary embolism and sudden cardiac death [2]. The molecular mechanisms underlying the pathogenesis and development of IPF are unclear, however molecules including chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, and non-coding RNA, and cellular processes, including apoptosis, senescence, hypoxia, endothelial-mesenchymal transition, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and alternative polyadenylation have been linked with the development of IPF [3]. Pirfenidone and nintedanib are the mainstays of current medical treatment of IPF, however they do not completely prevent or improve lung function. It is essential to find additional drugs that can effectively reduce the pro-fibrotic maturation of lung fibroblasts, and ultimately prevent IPF progression. Understanding the molecular mechanisms of IPF will aid in drug discovery. The wound healing response induced by Intrinsic risk factors including genetic susceptibility, aging, male sex, the lung microbiome, and comorbidities have been associated with the pathogenesis of IPF [8]. The susceptibility genes associated with the pathogenesis of IPF are currently classified into four categories: (1) genes related to alveolar stability (such as SFTPC, SFTPA1, SFTPA2);

[14] Are mast cells instrumental for fibrotic diseases?

  • Authors: C. Overed-Sayer, L. Rapley, T. Mustelin, D. Clarke
  • Year: 2014
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/706efd587a7fd74ae41d832bf0427b99755c3ea9
  • DOI: 10.3389/fphar.2013.00174
  • PMID: 24478701
  • PMCID: 3896884
  • Citations: 98
  • Influential citations: 6
  • Summary: The mast cell is discussed and its physiological role in tissue repair and remodeling, as well as its pathological role in fibrotic diseases such as IPF, where the process of tissue repairand remodeling is thought to be dysregulated.
  • Evidence snippets:
  • Snippet 1 (score: 0.505) > Idiopathic pulmonary fibrosis is a devastating disease for the patient. There is currently no effective treatment for this disease and the prognosis is bleak. As the term "idiopathic" indicates, the causes of the disease are unknown, as are the molecular mechanisms underpinning initiation and progression of the condition. Clearly, fibrotic processes play a key role in driving the relentless destruction of alveolar integrity, resulting eventually in a declining ability of the lung to oxygenate the blood. This decline is the root cause of the deteriorating health of the patient once the disease passes from its typically undiagnosed, early phase, into its clinically symptomatic phase. Within less than 3 years in most patients have lost much of their respiratory capacity and require drastic measures to survive. > The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for IPF, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of IPF. > On the positive side, with emerging new insights into the pathways and cell types involved in IPF come new opportunities for therapeutic intervention. Technologies for molecular profiling of patient tissue samples are already revealing many hitherto unexpected aspects of the disease pathology. Several new cell types, including the myofibroblast and the mast cell, offer therapeutic possibilities not previously exploited. However, the only conclusive way to determine if these cells are important for the pathogenesis of IPF is to target them with sufficiently powerful therapeutics and determine the impact on disease progression in phase 2 clinical trials. Another potentially helpful way to success may be that new therapeutics are first tested in other fibrotic conditions than IPF. Based on our current understanding of disease mechanisms, it appears likely that therapeutic interventions that are efficacious in one form of fibrotic disease will be efficacious in other fibrotic conditions. Thus, the clinically most feasible disease indication may serve as a first read-out to support the testing in more challenging indications, such as IPF. This may well be the case for mast cell-targeted therapies.

[15] The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

  • Authors: S. Kim, P. Cheresh, R. Jablonski, David B. Williams, D. Kamp
  • Year: 2015
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/2928a04f743ee87fdaa9439048757c7aa1d89ea3
  • DOI: 10.3390/ijms160921486
  • PMID: 26370974
  • PMCID: 4613264
  • Citations: 111
  • Influential citations: 3
  • Summary: A conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function is presented and suggests novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer.
  • Evidence snippets:
  • Snippet 1 (score: 0.502) > Pulmonary fibrosis is characterized by an over abundant accumulation of extracellular matrix (ECM) collagen deposition in the distal lung interstitial tissue in association with an injured overlying epithelium and activated myofibroblasts. Idiopathic pulmonary fibrosis (IPF) is the most common variety of lung fibrosis and carries a sobering mortality approaching 50% at 3-4 years [1]. Although many of the cellular and molecular mechanisms underlying the pathophysiology of lung fibrosis have emerged from numerous studies over the past several decades, the precise pathways involved, their regulation, and the role of crosstalk between cells are not fully understood. With the exception of two FDA-approved drug therapies (pirfenidone and nintenanib) emerging in the fall of 2014, there are no effective therapies for patients with IPF. Furthermore, these two drugs primarily slow disease progression rather than improve lung function or symptoms. A better understanding of the pathobiology of pulmonary fibrosis is critically important in the design of more useful therapies. > As will be reviewed herein, the extent of alveolar epithelial cell (AEC) injury, repair, and aging are emerging as critical determinants underlying pulmonary fibrosis. The purpose of this review is to highlight our current understanding of the causal role of AEC mitochondrial DNA (mtDNA) damage following oxidative stress in promoting AEC apoptosis and pulmonary fibrosis. Although oxidative mtDNA damage in other cell types (i.e., vascular endothelial cells, macrophages, fibroblasts, etc.) are likely important, we concentrate on the lung epithelium given its prominent role in the pathophysiology of lung fibrosis. In particular, we focus on asbestosis (pulmonary fibrosis arising following asbestos exposure) as it shares radiographic and pathologic features with IPF though IPF is more common and carries a worse prognosis. Our group is using the asbestos paradigm to better understand the pathophysiologic mechanisms underlying pulmonary fibrosis.

[16] Genome-Wide Transcriptional Response During the Development of Bleomycin-Induced Pulmonary Fibrosis in Sprague-Dawley Rats

  • Authors: Han-Jin Park, Mi-Jin Yang, Jung-Hwa Oh, Young-Su Yang, M. Kwon et al.
  • Year: 2010
  • Venue: Toxicological Research
  • URL: https://www.semanticscholar.org/paper/6c1484630c31abb392dd75998dcdefd244abf882
  • DOI: 10.5487/TR.2010.26.2.137
  • PMID: 24278517
  • PMCID: 3834473
  • Citations: 5
  • Influential citations: 1
  • Summary: Global gene expression analysis revealed significantly altered expression of genes in a time-dependent manner during the development of pulmonary fibrosis, and the expression of triggering receptor expressed on myeloid cells 2, secreted phosphoprotein 1, and several proteases was considerably induced in the lung after bleomycin treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.501) > Idiopathic pulmonary fibrosis is a consequence of abnormal tissue repair, which is characterized by extensive inflammation in the interstitial and alveolar spaces, proliferation of fibroblasts, and progressive fibrosis leading to the destruction of lung function (Selman et al., 2004). Pulmonary fibrosis involves cytokine networks and cellular interactions among several cell types, which results in increased collagen gene expression and collagen deposition in the lungs (Piguet et al., 1990;. Despite many investigations on the pathogenesis of pulmonary fibrosis and its relationship to immune cells, extracellular matrix repair, cytokines, and chemokines, the molecular mechanisms underlying this disease remain unclear (Zhang et al., 1994(Zhang et al., , 1996Kuwano et al., 2001;Gharaee-kermani et al., 2008). > Bleomycin is a useful chemotherapeutic antitumor drug, derived from Streptomyces verticillus; however, as a side effect, bleomycin treatment may lead to pulmonary fibrosis in humans and animals. Therefore, animal models of pulmonary fibrosis induced by the intratracheal instillation of bleomycin have been well established and widely used for studying the mechanisms underlying fibrosis and potential therapeutic agents (Jordana et al., 1988;Sakanashi et al., 1994;Moeller et al., 2008). Several studies using microarrays have been performed to evaluate gene expression patterns in the lungs after bleomycin instillation and identify the major genes involved in the progression of pulmonary fibrosis (Kaminski et al., 2000;Zuo et al., 2002;Katsuma et al., 2001;Pottier et al., 2007). These studies have provided information about genes that play central roles in the progression of fibrosis over time in a mouse model. Although genomic approaches using bleomycin-induced pulmonary fibrosis animal models have been useful for understanding the molecular mechanisms underlying fibrosis and for identifying fibrogenic markers, these approaches have limitations related to the vast data sets generated and the difficulty of replicating progressive fibrosis in animal models. Furthermore, recent studies aimed at eluc

[17] Exploring therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis

  • Authors: Yue Li, Congshan Jiang, Wenhua Zhu, Shemin Lu, Hongchuan Yu et al.
  • Year: 2024
  • Venue: Science Progress
  • URL: https://www.semanticscholar.org/paper/db2853a4caa1beb6b56a994ba01253577a388786
  • DOI: 10.1177/00368504241247402
  • PMID: 38651330
  • PMCID: 11036936
  • Citations: 6
  • Summary: The research platform, including cell and animal models involved in molecular therapy studies of idiopathic pulmonary fibrosis as well as the promising therapeutic targets and their development progress during clinical trials are reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.501) > Idiopathic pulmonary fibrosis is a chronic and progressive interstitial lung disease with a poor prognosis. Idiopathic pulmonary fibrosis is characterized by repeated alveolar epithelial damage leading to abnormal repair. The intercellular microenvironment is disturbed, leading to continuous activation of fibroblasts and myofibroblasts, deposition of extracellular matrix, and ultimately fibrosis. Moreover, pulmonary fibrosis was also found as a COVID-19 complication. Currently, two drugs, pirfenidone and nintedanib, are approved for clinical therapy worldwide. However, they can merely slow the disease's progression rather than rescue it. These two drugs have other limitations, such as lack of efficacy, adverse effects, and poor pharmacokinetics. Consequently, a growing number of molecular therapies have been actively developed. Treatment options for IPF are becoming increasingly available. This article reviews the research platform, including cell and animal models involved in molecular therapy studies of idiopathic pulmonary fibrosis as well as the promising therapeutic targets and their development progress during clinical trials. The former includes patient case/control studies, cell models, and animal models. The latter includes transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, lysophosphatidic acid, interleukin-13, Rho-associated coiled-coil forming protein kinase family, and Janus kinases/signal transducers and activators of transcription pathway. We mainly focused on the therapeutic targets that have not only entered clinical trials but were publicly published with their clinical outcomes. Moreover, this work provides an outlook on some promising targets for further validation of their possibilities to cure the disease. Graphical abstract Therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis.

[18] Idiopathic Pulmonary Fibrosis: Pathogenesis and the Emerging Role of Long Non-Coding RNAs

  • Authors: Marina R. Hadjicharalambous, M. Lindsay
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/ed2b2741fecf7bc8fcb573d9a0eea180bca01326
  • DOI: 10.3390/ijms21020524
  • PMID: 31947693
  • PMCID: 7013390
  • Citations: 57
  • Influential citations: 1
  • Summary: An overview of the emerging role of long non-coding RNAs (lncRNAs) in the development of IPF is provided.
  • Evidence snippets:
  • Snippet 1 (score: 0.496) > Fibrosis is a pathophysiological condition that can affect nearly every organ in the human body where irregular and excessive accumulation of scar tissue leads to organ failure and potentially death as seen in the final stages of fibrotic diseases such as pulmonary [1], cardiac [2], nephrotic [3], and hepatic fibrosis [4]. In combination with genetic factors, tissue injuries may provoke the development of fibrosis including exposure to damaging environmental stimuli such as irritants, smoke, radiation, viral, and bacterial infections [5,6]. > Idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disease (ILD) which is characterized by scar tissue accumulation, and therefore thickening of the normal lung walls, leading to impaired gas exchange and restricted ventilation. IPF is a disease of unknown aetiology, which makes the development of effective drug treatments particularly challenging [5]. Nonetheless, scientists have been intensively researching the molecular and cellular mechanisms of the disease and, although the pathogenesis of IPF is still unclear, several theories regarding the pathophysiology of IPF have been proposed [7]. > As is the case with most ILDs, inflammation was initially thought to be the major player in IPF until unresponsiveness to anti-inflammatory medications prompted the re-evaluation of this idiom [8,9]. However, the presence of immune cells in IPF lungs has been a consistent pathological finding and could be important in the development of the disease [10][11][12][13][14]. The histology of fibrotic lungs also indicates irreversible accumulation of scarred tissue characterized by collagen deposition and other alterations to the extracellular matrix (ECM) which dramatically remodels the lung architecture by stiffening the distal airspaces and parenchyma [5]. It has been suggested that lung fibrosis could be provoked by a number of different cell types including epithelial cells, fibroblasts, myofibroblasts, and immune cells [1].

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.